Comparison of the Calcium–Antagonistic Effects of Terodiline, Nifedipine and Verapamil

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Abstract
Studies were carried out on the Ca-antagonistic effects of terodiline and its enantiomers on the potassium-stimulated mesenteric and coronary arteries, on the spontaneous myogenic activity and norepinephrine- and acetylcholine-induced contractions of the protal vein and on electrically stimulated papillary muscle. The effects were compared with those of the Ca-antagonists, nifedipine and verapamil. Terodiline is relatively weak as a Ca-antagonist, having IC50-values between 5 .times. 10-6 and 2 .times. 10-5 M for all the tissues studied. Nifedipine is the most potent Ca-antagonist on vascular smooth muscle (IC50 3-6 .times. 10-9 M), but is considerably less potent on the papillary muscle (IC50 10-7 M). Verapamil is most potent on the papillary muscle (IC50 7 .times. 10-8 M) and the portal vein (IC50 6 .times. 10-8 M), but is 10 times less potent on the mesenteric and coronary arteries (IC50 3-5 .times. 10-7 M). Nifedipine is 1000 times and verapamil and (-)-terodiline 10 times more potent on the slow component of the K-induced contraction while (.+-.)- and (+)-terodiline are almost as active on the fast as on the slow component K-induced contractions on the mesenteric artery. Furthermore, (.+-.)- and (+)-terodiline are 10 times more potent in antagonizing acetylcholine- and norepinephrine-induced contractions, whereas (-)-terodiline is equally potent and nifedipine and verapamil are 10 times more potent in blocking the myogenic activity of the portal vein. On the Ca2+-depleted portal vein the contractions induced by K+, together with Ca2+, were antagonized by terodiline, nifedipine and verapamil. However, nifedipine and verapamil, but not terodiline, in concentrations which blocked the maximal norepinephrine-induced response in non-depleted muscle, antagonized the contractions induced by norepinephrine together with Ca2+ in the Ca2+ depleted portal vein. These results show that terodiline blocks the uptake of Ca2+ and, in addition, blocks the utilization of some intracellular stores of Ca2+.